Method for determining glucose concentration in human blood

ABSTRACT

Measuring the impedance of a human body region at a high frequency (Z HF ) and a low frequency (Z LF ). Z HF  is used to obtain the value of the volume of fluid in the tissues of the region. Z LF  is used to obtain the value of the volume of extracellular fluid in the tissues. The increase in the metabolic component in the volume of extracellular fluid is determined by the increase of the volume of all of the fluid in comparison with the previous measurement, determining the increase in the volume of extracellular fluid in comparison with the previous measurement and subsequently calculating the difference between the increases in the volume of all of the fluid and the volume of extracellular fluid. The glucose concentration G(t k ) is determined by adding the amount of increase in the glucose concentration and the value of the glucose concentration determined at the previous measuring stage.

RELATED APPLICATIONS

This Application is a Continuation application of InternationalApplication PCT/RU2013/000144, filed on Feb. 22, 2013, which in turnclaims priority to Russian Patent Applications No. RU2012106461, filedFeb. 24, 2012, both of which are incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

The invention refers to non-surgical methods for medical examination ofhuman health, namely, to methods for determining glucose concentrationin human blood as a result of measuring the impedance of human bodypart.

BACKGROUND OF THE INVENTION

Non-invasive methods for determining glucose concentration in humanblood based on measuring the electrical impedance of a human body partor impedance components are known.

For example, a method for the indication of sugar content in human bloodis known [RU Pat. No. 2073242, G01N33/4, 1997], with which sugar contentlevel is determined based on variation of dielectric permeability of afinger placed in the electrical field of transducer.

A method for monitoring the amount of sugar in human blood is also known[RU Pat. No. 2088927, G01N33/49, 1997], with which the measurement istaken by changing the reactance of oscillating circuits included in thesecondary circuits of high-frequency generator via direct action ofhuman upon oscillating circuits elements. With this method, the amountof sugar in blood is determined based on variation of current in thesecondary circuits of high-frequency generator.

Another method is known [U.S. Pat. No. 5,792,668, G01N27/00, 1998], withwhich spectral analysis of high-frequency radiation reflected by humanbody or passing through the human body is conducted. The phase shiftbetween direct and reflected (or transmitted) waves, which characterizesthe reactive component of electrical impedance, represents a parameterto be measured by this method. The concentration of substances containedin the blood (in particular, glucose concentration) is determined basedon measured parameters of phase spectrum.

Another method is known, which was embodied in a device described in theRU Pat. No. 9703U1, A61B5/00, 1999. Glucose concentration is determinedby this device based on measurement of human body region impedance attwo frequencies, determining capacitive component of impedance andconverting the obtained value of capacitive component into glucoseconcentration in patient's blood.

A method for measuring glucose concentration in human bloodnon-invasively is known [U.S. Pat. No. 6,517,482, A61B5/00, 2003]. Themethod is based on measuring impedance between two electrodes at anumber of frequencies and deriving the value of glucose concentration onthe basis of measured values.

Another method for determining glucose concentration in bloodnon-invasively is known, which involves measuring electric transferfunctions by means of two pairs of four-electrode sensors [RU Pat. No.2342071, A61B5/053, 2008]. The concentration of glucose in blood isdetermined based mathematical model specified in advance.

Another method for determining glucose concentration in human blood isalso known [U.S. Pat. No. 7,050,847, A61B5/00, 2006], with whichimpedance of a human body area is measured at different frequencies bymeans of sensors. Impedance value at high frequencies is related tofluid volume in body tissues, while impedance value at lowfrequencies—to volume of extracellular fluid. Parameters of biologicalfluids in the human body are determined based on the measured values,and then glucose concentration in human blood is derived from theseparameters.

However, the above-described methods are characterized by one commondisadvantage—namely, the values of glucose concentration in human bloodobtained through the use of these methods rank below the values obtainedusing direct invasive methods in terms of measurement accuracy. At thesame time, invasive methods, which require taking samples of blood, rankbelow non-invasive ones in terms of convenience and safety.

An engineering problem to be solved by the present invention consists inworking out a non-invasive method for continuous determination ofglucose concentration in human blood that is characterized by higheraccuracy as compared to currently known non-invasive methods.

SUMMARY OF THE INVENTION

A method of measuring of a concentration of blood glucose in a human,the method comprising:

using spaced apart electrodes attached to a region of a body of thehuman to successively measure values of high frequency impedance and lowfrequency impedance of the region at predetermined time intervals;

using a measured value of the high frequency impedance to determine anestimate of a volume of fluid in tissue of the region between theelectrodes;

using a measured value of the low frequency impedance to determine anestimate of a volume of an extracellular fluid in the tissue in theregion between the electrodes;

determining an increment of a metabolic component of the volume of theextracellular fluid by:

determining an increment of the estimate of the volume of the fluidrelative to a previously measured value of the volume of the fluid;

determining an increment of the estimate of the volume of theextracellular fluid relative to a previously measured value of thevolume of the extracellular fluid;

determining a difference between the increment of the estimate of thevolume of the fluid and the increment of the estimate of the volume ofthe extracellular fluid;

determining an increment of the concentration of the blood glucose bynormalizing the increment of the metabolic component of the volume ofthe extracellular fluid; and

determining the concentration of the blood glucose by adding up theincrement of the concentration of the blood glucose and a previouslydetermined concentration of the blood;

wherein determining a concentration of the blood glucose at a first timeinterval comprises adding up an increment of the concentration at thefirst interval of time and an initial blood glucose concentration.

The principal physics of the method consists in measuring the volume offluid in a human body region. The water in human body accounts for 70%of body weight, and it is not present in the human body as a singlespace, but distributed among body tissues. Vascular walls and cellmembranes (out of which consist all tissues of human body) serve asboundaries for fluids. It is generally accepted to distinguish threewater spaces: intracellular fluid, intravascular fluid (blood plasmafluid) and intercellular fluid (fluid that fills the intercellularspace).

The intracellular fluid or fluid contained within tissue cells and redblood cells accounts for approximately 30-40% of human body weight.

Intravascular fluid and intercellular fluid form the space ofextracellular fluid, which accounts for about 20% of human body weight.

Substances intended for sustaining the life of cells or products oftheir vital activity that are to be disposed of or reprocessed insidehuman body are present in each type of fluid. These substances movethrough cell membranes from one space to another in the process of vitalactivity of the human body. Osmotic pressure that depends upondifference in concentration (concentration gradient) of substances ondifferent sides of the membrane represents one of the driving forces forthis motion.

A dynamic equilibrium of metabolic processes is observed in the state ofrest. The appearance of concentration gradient of osmotic pressure(e.g., together with glucose inflow from gastrointestinal tract afterfood intake) forces water to move though cell membrane in the directionof space characterized by higher concentration of solids dissolved init. The volumes of water sectors are changed as a result of thisprocess. But then regulatory mechanisms striving to restore thedisturbed equilibrium of these spaces come into action. In other words,changes of water spaces volumes of human body have characteristic(cyclic) specific features. These specific features can be used asindicators of the character of metabolic processes in the human body,e.g. increase of glucose concentration in human blood after food intake.

The basis of the method consists in estimating an increase or decreaseof glucose concentration in the blood based on changes of water spacesin the human body in time, which is determined in the course of periodicmeasurements of impedance of a human body region.

The following steps are performed in particular embodiments of themethod.

Initial value of glucose concentration in human blood is determined inthe beginning of measurements (using an alternative method—eitherinvasive or non-invasive one). This absolute value is individual forevery human being and it determines not only the nature of dynamics ofglucose concentration changes, but also its absolute values duringdifferent periods of life activity of human being.

In particular, at least two electrodes installed at a certain distancefrom one another (preferably on peripheral body regions—e.g. a finger oran arm) can be used for measuring the impedance of a human body region.

Measurements of impedance of a human body region at high and lowfrequencies are taken with a predetermined time interval from 1 sec to10 min. For the sake of convenience of hardware implementation of themethod these time interval should be equal.

The moment of food intake is recorded during measurement taking, andthis fact is used to adjust the indicators of dynamics of glucose supplyinto the human body.

Specifically, the following parameters are determined when implementingthe method based on values of human body region impedance measured athigh and low frequencies at points in time t_(k):

1) Volume of fluid contained in the tissues of the human body regionbetween electrodes W_(sum)(t_(k)) is calculated from the equation:

W _(sum)(t _(k))=A·L ² /Z _(HF)(t _(k)),

where: L—the distance between two electrodes;

Z_(HF)(t_(k)) is the high frequency HF impedance measured at time t_(k);

A is a calibration factor determined as:

A=V _(sum) ·Z _(HF) /L ²,

where: V_(sum) is a preliminary determined value of the volume of fluidin the tissue in the region between the electrodes;

Z_(HF)—preliminary determined high frequency HF impedance;

2) W_(out)(t_(k)) is the volume of the extracellular fluid in the tissueof the region between the electrodes determined according to thefollowing equation:

W _(out)(t _(k))=B·L ² /Z _(LF)(t _(k)),

where: Z_(LF)(t_(k)) is the low frequency LF impedance measured at timet_(k);

B is a calibration factor, calculated as:

B=V _(out) ·Z _(LF) /L ²;

where: V_(out)—preliminary determined volume of the extracellular fluidin region between the electrodes;

Z_(LF)—preliminary determined low-frequency LF impedance;

3) ΔW_(osm)(t_(k)) is the increment of the metabolic componentdetermined as:

ΔW _(osm)(t _(k))=[W _(sum)(t _(k-1))−W _(sum)(t _(k))]−K _(a) [W_(out)(t _(k-1))−W _(out)(t _(k))],

where: W_(sum)(t_(k-1))—volume of fluid in the tissues of the human bodyregion between the electrodes measured at time t_(k-1);

W_(out) (t_(k-1))—volume of extracellular fluid in the tissues of thehuman body region between the electrodes measured at time t_(k-1);

K_(a) is a factor dependent on a human hematocrit volume selected from arange from 1.2 to 2.1;

4) ΔG(t_(k)) is the increment of the concentration of the blood glucosedetermined as:

ΔG(t _(k))=ΔW _(osm)(t _(k))·K _(E) ·K _(PR) /K _(g),

where: K_(g) is a normalizing factor ranging from 0.005 l²millimole⁻¹ to0.006 l²millimole⁻¹;

K_(E) is a factor selected from a range of 0.23 to 0.4 before a mealintake, and selected from a range of 0.6 to 1.0 after the meal;

K_(PR) is a factor corresponding to measuring the concentration of theglucose in blood from 20 min to 45 min after the meal intake andwherein:

K_(PR)=1, if ΔW_(osm)(t_(k))is more than 0;

K_(PR)=−1, if ΔW_(osm)(t_(k)) is less than 0.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is illustrated with the following graphic drawings.

FIG. 1A is a graph showing variation of shows the results of determiningglucose concentration in the blood for the first volunteer.

FIG. 1B is a graph showing measured values of impedance and temperaturefor the first volunteer.

FIG. 2A is a graph showing variation of shows the results of determiningglucose concentration in the blood for the second volunteer.

FIG. 2B is a graph showing measured values of impedance and temperaturefor the second volunteer.

FIG. 3A is a graph showing variation of shows the results of determiningglucose concentration in the blood for the third volunteer.

FIG. 3B is a graph showing measured values of impedance and temperaturefor the third volunteer.

FIGS. 1 a, 2 a and 3 a show the graphs of variation of glucoseconcentration determined through the use of different methods, includingthe method of the present invention, while FIGS. 1 b, 2 b and 3 b showgraphs of measured values of impedance and temperature.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The method is implemented in the following way.

Two electrodes are secured on a human body region apart from oneanother—at distance L . It is preferable to secure electrodes onperipheral body regions—e.g. on an arm, specifically, on forearm orfinger. The best result will be obtained in the case of using annularelectrodes embracing forearm or a finger

Since the method according to the invention claimed herein is based oncalculating the values of the increment of glucose concentration inhuman blood followed by summing up the calculated values, prior totaking measurements of impedance, blood glucose concentration should bemeasured (using any other method—invasive or non-invasive one), and thevalue of thus measured impedance is taken as the initial one.

Impedance of a human body region is measured between electrodes at twofrequencies: high frequency HF and low frequency LF. High frequency HFis chosen from the range from 200 kHz to 2 MHz; low frequency LF ischosen from the range from 20 kHz to 80 kHz. Electrical impedance ofcomponents of electrical impedance of body region tissues can bemeasured using one of the known methods, specifically, by radiatinghigh-frequency oscillations and subsequent measuring the impedance bymeans of capacitive sensors. Impedance of a human body region ismeasured at time intervals chosen from the range from 1 sec to 10 min.

A moment of food intake (characterizing glucose supply into the humanbody from the outside) is recorded in the course of measurements. Thisis done to derive the increment of metabolic component of the volume ofextracellular fluid related to glucose, taking into account the timethat have elapsed since the recorded moment of food intake beginning.

Based on the initial glucose concentration volume in human blood,current successive measurements of impedance of a human body region athigh and low frequencies, and taking into account the time moment offood intake, glucose concentration in human blood is derived as follows.

1. The volume of fluid contained in a human body region between theelectrodes W_(sum)(t^(k)) is derived based on impedance value for humanbody region measured at high frequency HF at point in timet_(k)−Z_(HF)(t_(k)) , taking into account distance L between theelectrodes, as follows:

W _(sum)(t _(k))=A·L ² /Z _(HF)(t _(k)),

where: A—calibration factor, calculated from the formula:

A=V _(sum) ·Z _(HF) /L ².

Here, V_(sum)—value (obtained in advance) of the volume of fluidcontained in the tissues of human body region between the electrodes.This value can be, for instance, calculated using anatomicalrelationships of the human body region chosen for impedance measuring.Also, the value of impedance of a human body region measured at highfrequency Z_(HF) (and obtained in advance prior to the beginning ofmeasurements intended for determining glucose concentration in humanblood according to the invention claimed herein) is used for derivingcalibration factor A.

2. The volume of extracellular fluid contained in the tissues of a humanbody region between the electrodes W_(out)(t_(k)) is derived based onimpedance value for human body region measured at low frequency LF atpoint in time t_(k)—Z_(LF)(t_(k)), taking into account distance Lbetween the electrodes, as follows:

W _(out)(t _(k))=B·L ² /Z _(LF)(t _(k)),

where: B—calibration factor, calculated from the formula:

B=V _(out) ·Z _(LF) /L ².

Here, V_(out)—value (obtained in advance) of the volume of extracellularfluid contained in the human body region between the electrodes. Thisvalue can be, for instance, calculated using anatomical relationships ofthe human body region chosen for impedance measuring. Also, the value ofimpedance of a human body region measured at low frequency Z_(LF) isused for determining the calibration factor B. This impedance value isdetermined in advance prior to measurements of glucose concentration inhuman blood according to the present invention.

3. Then obtained value of volume of fluid contained in the tissues ofthe human body region between electrodes, and volume of extracellularfluid contained in the tissues of the human body region betweenelectrodes, are used for calculating the increment of metaboliccomponent of the extracellular fluid volume ΔW_(osm)(t_(k)). The valuesof fluid volumes obtained for measurements of impedance at point in timet_(k) and for the previous measurement at point in time t_(k-1) are usedfor this calculation. The increment of metabolic component ofextracellular fluid volume is calculated from the formula:

ΔW _(osm)(t _(k))=[W _(sum)(t _(k-1))−W _(sum)(t _(k))]−K _(a) [W_(out)(t_(k-1))−W _(out)(t _(k))],

where: W_(sum)(t_(k))—volume of fluid contained in the tissues of thehuman body region between the electrodes, for the current measurementtaken at point in time t_(k);

W_(sum)(t_(k-1))—volume of fluid contained in the tissues of the humanbody region between the electrodes, for the previous measurement takenat point in time t_(k-1);

W_(out)(t_(k))—volume of extracellular fluid contained in the tissues ofthe human body region between the electrodes, for the currentmeasurement taken at point in time t_(k);

W_(out)(t_(k-1))—volume of extracellular fluid contained in the tissuesof the human body region between the electrodes, for the previousmeasurement taken at point in time t_(k-1);

K_(a)—factor dependent on the value of human hematocrit (this factor ischosen from the range from 1.2 to 2.1).

4. The value of the increment of glucose concentration in human blood isdetermined based on the obtained value of ΔW_(osm)(t_(k)) taking intoaccount the moment of food intake:

ΔG(t _(k))=ΔW _(osm)(t _(k))·K _(E) ·K _(PR) /K _(g),

where: K_(g)—the normalizing factor chosen from the range from 0.005l²millimole⁻¹ to 0.006 l²millimole⁻¹.

K_(E)—factor dependent on food intake; when determining glucoseconcentration in human blood prior to food intake, K_(E) value is chosenfrom the range from 0.23 to 0.4, and when determining glucoseconcentration in human blood after food intake, K_(E) value is chosenfrom the range from 0.6 to 1.0;

K_(PR)—factor used for determining glucose concentration in human bloodin the time period from 20 to 45 minutes after food intake, with thisfactor taking the value either 1 or −1 depending on the sign of the saidincrement of metabolic component of the extracellular fluid volumeaccording to the following rule:

K_(PR)=1, if the said increment of metabolic component of theextracellular fluid volume ΔW_(osm)(t_(k)) is greater than 0,

K_(PR)=−1, if the said increment of metabolic component of theextracellular fluid volume ΔW_(osm)(t_(k)) is less than 0.

5. The final value of glucose concentration in human blood by point intime t_(k) is derived as follows:

${{G\left( t_{k} \right)} = {G_{0} + {\sum\limits_{i = 1}^{k}\; {\Delta \; {G\left( t_{i} \right)}}}}},$

where: G₀—initial value of glucose concentration in human blood;

ΔG(t_(i))—values of all increments of glucose concentration in humanblood obtained from the beginning of measurements till point in timet_(k) , where i={1,k}.

Thus, knowing the initial value of glucose concentration in human bloodG₀ and periodically taking measurements of impedance of the human bodyregion at high and low frequencies—Z_(HF)(t_(k)) and Z_(LF)(t_(k)), onecan derive the current value of glucose concentration in human blood.The present invention can be embodied as quite simple measuring devicecapable of calculating of the above-indicated parameters characterizingchanges in volumes of water spaces in human tissues, and finally, thecurrent value of glucose concentration in human blood, including theoption of taking into account the individual physiological features ofhuman being and moments of food intake.

EXAMPLES Example 1 Processing of Measurement Data for Healthy Volunteer#1

A 38-year-old healthy male, took a meal (food load) of 300 g of sweetbeverage (Pepsi Cola). FIG. 1 b shows the graphs of impedance valuevariation Z_(HF) and Z_(LF) and temperature T° C. recorded by the sensorlocated on the forearm, while FIG. 1 a shows the graph of variation ofglucose concentration in the blood of Volunteer #1. Dots indicate valuesof blood sample taken during the measurements (Roche Accu-Chek Activeglucometer was used). The mean error for the measurement interval of 150minutes was equal to 6.8%.

Example 2 Processing of Measurement Data for Healthy Volunteer #2

A 45-year-old healthy male, took a meal (food load) of two 200 g glassesof sweet beverage (Pepsi Cola). FIG. 2 b shows the graphs of impedancevalue variation Z_(HF) and Z_(LF) and temperature T° C. recorded by thesensor located on the forearm, while FIG. 2 a shows the graph ofvariation of glucose concentration in the blood of Volunteer #2. Dotsindicate values of blood sample taken during the measurements (RocheAccu-Chek Active glucometer was used). The mean error for themeasurement interval of 140 minutes was equal to 7.2%.

Example 3 Processing of Measurement Data for Healthy Volunteer #3

A 42-year-old healthy male, took a combined meal (food load) of 200 g ofsweet beverage (Pepsi Cola) and banana. FIG. 3 b shows the graphs ofimpedance value variation Z_(HF) and Z_(LF) and temperature T° C.recorded by the sensor located on the forearm, while FIG. 3 a shows thegraph of variation of glucose concentration in the blood of Volunteer#3. Dots indicate values of blood sample taken during the measurements(Roche Accu-Chek Active glucometer was used). The mean error for themeasurement interval of 150 minutes was equal to 9.5%.

The conducted tests showed that the method claimed herein ischaracterized by lesser error when determining the value of glucoseconcentration in human blood as compared to the known non-invasivemethods.

What is claimed is:
 1. A method of measuring of a concentration of bloodglucose in a human, the method comprising: using spaced apart electrodesattached to a region of a body of the human to successively measurevalues of high frequency impedance and low frequency impedance of theregion at predetermined time intervals; using a measured value of thehigh frequency impedance to determine an estimate of a volume of fluidin tissue of the region between the electrodes; using a measured valueof the low frequency impedance to determine an estimate of a volume ofan extracellular fluid in the tissue in the region between theelectrodes; determining an increment of a metabolic component of thevolume of the extracellular fluid by: determining an increment of theestimate of the volume of the fluid relative to a previously measuredvalue of the volume of the fluid; determining an increment of theestimate of the volume of the extracellular fluid relative to apreviously measured value of the volume of the extracellular fluid;determining a difference between the increment of the estimate of thevolume of the fluid and the increment of the estimate of the volume ofthe extracellular fluid; determining an increment of the concentrationof the blood glucose by normalizing the increment of the metaboliccomponent of the volume of the extracellular fluid; and determining theconcentration of the blood glucose by adding up the increment of theconcentration of the blood glucose and a previously determinedconcentration of the blood; wherein determining a concentration of theblood glucose at a first time interval comprises adding up an incrementof the concentration at the first interval of time and an initial bloodglucose concentration.
 2. The method according to claim 1, wherein theinitial blood glucose concentration is determined invasively.
 3. Themethod according to claim 1, wherein at least two spaced apartelectrodes attached to the region of the body of the human are used. 4.The method according to claim 3, wherein the at least two spaced apartelectrodes are attached to the peripheral body regions as an arm or afinger.
 5. The method according to claim 1, wherein the predeterminedtime intervals range from 1 s to 10 min.
 6. The method according toclaim 1, wherein: W_(sum) (t_(k)) is the volume of fluid in tissue ofthe region between the electrodes, determined according to the followingequation:W _(sum)(t _(k))=A·L ² /Z _(HF)(t _(k)), wherein: L—is a distancebetween the two electrodes; Z_(HF)(t_(k)) is the high frequency HFimpedance measured at time t_(k); A—is a calibration factor determinedas A=V_(sum)·Z_(HF)/L²; wherein V_(sum)—is a preliminary determinedvalue of the volume of fluid in the tissue in the region between theelectrodes; Z_(HF)—preliminary determined high frequency HF impedance;W_(out)(t_(k)) is the volume of the extracellular fluid in the tissue ofthe region, between the electrodes determined according to the followingequation:W _(out)(t_(k))=B·L ² /Z _(LF)(t _(k)), wherein Z_(LF)(t_(k))—is the lowfrequency LF impedance measured at time t_(k); B—is a calibrationfactor, calculated as B=V_(out)·Z_(LF)/L²; wherein V_(out)—preliminarydetermined volume of the extracellular fluid in region;Z_(LF)—preliminary determined low-frequency LF impedance;ΔW_(osm)(t_(k)) is the increment of the metabolic component determinedas:ΔW _(osm)(t _(k))=[W _(sum)(t _(k-1))−W _(sum)(t _(k))]−K _(a) [W_(out)(t _(k-1))−W _(out)(t _(k))], wherein W_(sum)(t_(k-1)) is thevolume of the fluid in the tissue measured at time t_(k-1);W_(out)(t_(k-1)) is the volume of the extracellular fluid measured attime t_(k-1); K_(a) is a factor dependent on a human hematocrit volumeselected from a range from 1.2 to 2.1; ΔG(t_(k))is the increment of theconcentration of the blood glucose determined as:ΔG(t _(k))=ΔW _(osm)(t _(k))·K _(E) ·K _(PR) /K _(g), wherein K_(g) is anormalizing factor ranging from 0.005 l²millimole⁻¹ to 0.006l²millimole⁻¹; K_(E) is a factor selected from a range of 0.23 to 0.4before a meal intake, and selected from a range of 0.6 to 1.0 after themeal; K_(PR) is a factor corresponding to measuring the concentration ofthe glucose in blood from 20 min to 45 min after the meal intake andwherein: K_(PR)=1 if ΔW_(osm)(t_(k))is more than 0; and K_(PR)=−1 ifΔW_(osm)(t_(k)) is less than 0.